Androgen ablation therapy is the mainstay for prostate cancer (PC) treatment. However, it is not curative, as many patients progress to a castration-resistant stage of prostate cancer (CRPC). In fact, prostate cancer progression is dependent on continuous androgen receptor (AR) signaling and transcriptional activity. Thus, strategies designed to effectively inhibit androgen receptor transcriptional activity and signaling, are at the forefront of current research in prostate cancer. The importance of the androgen receptor in prostate cancer disease progression is highlighted by the fact that many recent therapies are designed to target the androgen axis, such as the androgen receptor antagonist enzalutamide (formerly MDV3100) (see, e.g., Hoffman-Censits & Kelly, Clin Cancer Res 19, 1335 (Mar. 15, 2013); Tran et al., Science 324, 787 (May 8, 2009)), and the CYP17 inhibitor abiraterone (Bono et al., N Engl J Med 364, 1995 (May 26, 2011)), which inhibits androgen synthesis. However, resistance to all forms of androgen deprivation therapy, including these next-generation compounds, occurs eventually and results in disease progression. Despite androgen ablation, castration-resistant prostate cancer (CRPC) remains androgen receptor driven due to several mechanisms including androgen receptor gene amplification, in situ androgen production and the presence of ligand-independent AR splice variants which localize to the nucleus and are constitutively active (Nelson, J Clin Oncol 30, 644 (Feb. 20, 2012); Locke et al., Cancer Res 68, 6407 (Aug. 1, 2008); Chen et al., Nat Med 10, 33 (January, 2004); Nadiminty & Gao, World J Urol 30, 287 (June, 2012)).
A major challenge in the clinical management of castration-resistant prostate cancer is that currently there is no biomarker that predicts clinical efficacy of chemotherapy. The taxanes represent the only class of cancer chemotherapeutics demonstrated to prolong survival in castration-resistant prostate cancer. Despite the clinical success of taxanes, treatment efficacy can be transient and the development of clinical taxane resistance is the major cause of cancer-related death. An important clinical question remains as to why patients who fail treatment with one taxane respond to another, and how clinicians can anticipate progression and proactively switch treatment.
New methods for detecting what type of therapeutic intervention is appropriate for a particular patient are needed.